The invention includes novel chemical compounds having specific binding in a biological system and capable of being used for positron emission tomography (PET).
The ability of analog compounds to bind to localized ligands within the body makes it possible to utilize such compounds for in situ imaging of the ligands by PET, SPECT and similar imaging methods. In principle, nothing need be known about the nature of the ligand, as long as binding occurs, and such binding is specific for a class of cells, organs, tissues or receptors of interest. PET imaging is accomplished with the aid of tracer compounds labeled with a positron-emitting isotope (Goodman, M. M. Clinical Positron Emission Tomography, Mosby Yearbook, 1992, K. F. Hubner et al., Chapter 14). For most biological materials, suitable isotopes are few. The carbon isotope, [11C], has been used for PET, but its short half-life of 20.5 minutes limits its usefulness to compounds that can be synthesized and purified quickly, and to facilities that are proximate to a cyclotron where the precursor [11C] starting material is generated. Other isotopes have even shorter half-lives. [13N] has a half-life of 10 minutes and [15O] has an even shorter half-life of 2 minutes. The emissions of both are more energetic than those of [11C]. Nevertheless, PET studies have been carried out with these isotopes (Hubner, K. F., in Clinical Positron Emission Tomography, Mosby Year Book, 1992, K. F. Hubner, et al., Chapter 2). A more useful isotope,[18F], has a half-life of 110 minutes. This allows sufficient time for incorporation into a radio-labeled tracer, for purification and for administration into a human or animal subject. In addition, facilities more remote from a cyclotron, up to about a 200 mile radius, can make use of [18F] labeled compounds. Disadvantages of [18F] are the relative scarcity of fluorinated analogs that have functional equivalence to naturally-occurring biological materials, and the difficulty of designing methods of synthesis that efficiently utilize the starting material generated in the cyclotron. Such starting material can be either fluoride ion or fluorine gas. In the latter case only one fluorine atom of the bimolecular gas is actually a radionuclide, so the gas is designated 18F-F. Reactions using 18F-F as starting material therefore yield products having only one half the radionuclide abundance of reactions utilizing K18F as starting material. On the other hand, [18F] can be prepared in curie quantities as fluoride ion for incorporation into a radiopharmaceutical compound in high specific activity, theoretically 1.7 Ci/nmol using carrier-free nucleophilic substitution reactions. The energy emission of [18F] is 0.635 MeV, resulting in a relatively short, 2.4 mm average positron range in tissue, permitting high resolution PET images.
Use of [18F] labeled compounds in PET has been limited to a few analog compounds. Most notably, [18F]-fluorodeoxyglucose has been widely used in studies of glucose metabolism and localization of glucose uptake associated with brain activity. [18F]-L-fluorodopa and other dopamine receptor analogs have also been used in mapping dopamine receptor distribution.
Other halogen isotopes can serve for PET or for conventional tracer labeling. These include 75Br, 76Br, 77Br and 82Br which have usable half-lives and emission characteristics. In general, the chemical means exist to substitute any halogen moiety for the described isotopes. Therefore, the biochemical or physiological activities of any halogenated homolog of the described compounds are now available for use by those skilled in the art, including stable isotope halogen homologs. Astatine can be substituted for other halogen isotopes; [210At] emits alpha particles with a half-life of 8.3 h. At-substituted compounds are therefore useful for tumor therapy, where binding is sufficiently tumor-specific.
Dopamine transporters (DAT) are proteins that reside on the membrane of the nerve terminals of the presynaptic mesolimbic dopaminergic neurons. The DAT serves to remove dopamine from the synapse, a process which helps regulate central nervous system (CNS) dopamine neurotransmission. A decrease in DAT density in the striatum has been associated with Parkinson""s disease. Inhibition of the re-uptake of dopamine at the DAT has been implicated with the reinforcing properties of cocaine.
Abnormalities in CNS dopaminergic neurotransmission have been implicated in movement disorders such as Parkinson""s disease. This disorder has been shown to be caused by a significant decrease in the synthesis and transmission of dopamine which results from a degeneration of dopamine neurons in the substantia nigra and striatum. Drugs such as levodopa have been found to provide a clinical benefit only early in the course of Parkinson""s disease by supplementing the brain""s supply of dopamine. During the progression of the disease the effectiveness of drug therapy diminishes. Efforts to identify potentially more Gleffective therapeutic strategies for preventing or slowing degeneration of dopamine neurons has resulted in the development of neuroprotective agents. Monoamine oxidase inhibitors such as deprenyl appeared in early clinical trials to provide some benefit. A potentially more promising therapy for patients with Parkinson""s disease is transplantation of human fetal mesencephalic tissue. The implantation of human fetal brain tissue in a small number of patients has been reported to result in the improvement of their overall functions. Longitudinal studies with a radiopharmaceutical for providing quantitative information on dopamine neuronal density using imaging technology would be valuable in determining the efficacy of the therapeutic strategies described above. In vivo imaging studies in normal volunteersand patients with Parkinson""s disease using positron emission tomograph (PET) involving 6-[18F]fluorodopa has provided a measure of dopamine synthesis and storage in vesicles of presynaptic neurons in the basal ganglia. However, a significant amount of peripheral [18F]fluorodopa metabolism, transport and nonspecific binding of radiometabolites in the brain result in low striatal to cerebellum ratios of 2:1. Loss of dopaminergic neurons in the substantia nigra in patients with Parkinson""s disease has also shown to result in a corresponding loss of dopamine transporter sites in the membrane of striatal presynaptic dopaminergic neurons. Because the dopamine transporter plays a pivotal role in dopamine neurotransmission, the development of radiopharmaceuticals radiolabeled with positron emitting isotopes which exhibit pronounced brain uptake, very high selectivity and affinity for the transporter, and low nonspecific binding would be excellent for the measurement of the density of presynaptic dopamine transporter sites by positron emission tomography. To meet this need, the present application discloses a new series of brain imaging agents, typical of which are (N-CE)4xe2x80x2-fluorobut-2-en-1-yl-2xcex2-carbomethoxy-3xcex2-(4-substituted-phenyl)nortropane (FBNT) and (n-(E)-4xe2x80x2-fluorobut-2-en-1-yl-2xcex2-carbomethoxy-3xcex2-(4-chlorophenyl)nortropane (FBCINT). When labeled with the positron emitting radioisotope fluorine-18, a compound of the invention can be used as a diagnostic imaging agent to measure CNS neuronal function in the brain of a patient suffering from Parkinson""s disease and cocaine addiction.
The invention provides fluoroalkenyl nortropanes having the following general structure (Formula I): 
where R is C2-C6 mono- or multi-unsaturated hydrocarbon having one or more ethylene, acetylene or allene groups,
a is 18 or 19, and
X is H or halogen
Compounds of the invention bind specifically and preferentially to dopamine transporter (DAT). 18F-labeled compounds of the invention are useful for positron emission tomography (PET) imaging of dopaminergic neurons. Unlabeled compounds have pharmacological utility as cocaine analogs. Both E and Z isomers of the alkenyl moiety can be synthesized. Substituents on the phenyl ring can be H or halogen. The invention is described in detail by reference to an exemplary compound having an F-butenyl group substituted on the bridge nitrogen. CR is C2H2.
Examples of suitable R groups include:
and the like, including both E and Z isomers, where possible.
In particular are provided compounds wherein R is CHxe2x95x90CH, a is 18, and X is selected from the group consisting of H, Br, Cl, I and F in the 4xe2x80x2 position.
Methods of synthesis are described that permit last step substitution of the halogen radiolabel such that the final compound can be purified to high specific activity. As a result, the useable half-life of the isotope has been maximized.
Methods are provided for conducting positron emission tomography imaging of a subject comprising:
1) administering to the subject an image-generating amount of a compound of formula I which contains at least one radioactive halogen and
2) measuring the distribution within the subject of the compound by positron emission tomography.